Identification
- Summary
Tazemetostat is a methyltransferase inhibitor indicated to treat patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
- Brand Names
- Tazverik
- Generic Name
- Tazemetostat
- DrugBank Accession Number
- DB12887
- Background
Tazemetostat is a methyltransferase inhibitor used to treat metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.6 Tazemetostat was first named in literature as EPZ-6438.5
Tazemetaostat was granted FDA approval on 23 January 2020.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tazemetostat (DB12887)
- Weight
- Average: 572.75
Monoisotopic: 572.336255913 - Chemical Formula
- C34H44N4O4
- Synonyms
- Tazemetostat
- Tazémétostat
- Tazemetostatum
- External IDs
- E 7438
- EPZ-6438
Pharmacology
- Indication
Tazemetostat is indicated to treat adult and pediatric patients 16 years and older with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection.6 It is also indicated to treat adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an IZH2 mutation and who have received at least 2 prior systemic therapies.6 Additionally, it is indicated in adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.6
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Locally advanced epithelioid sarcoma •••••••••••• •••••• ••••••••• ••• •••••••• ••• •••••••• ••••••••• •••••• Treatment of Metastatic epithelioid sarcoma •••••••••••• •••••• ••••••••• ••• •••••••• ••• •••••••• ••••••••• •••••• Treatment of Refractory follicular lymphoma •••••••••••• ••••• •••••• Treatment of Refractory follicular lymphoma •••••••••••• ••••• •••• •••• ••••••••• •• ••••• •••••••• ••••••••• •••••• Treatment of Relapsed follicular lymphoma •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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Tazemetostat is a methyltransferase inhibitor that prevents hyper-trimethylation of histones and inhibits cancer cell de-differentiation.6 The duration of action is long as it is given twice daily.6 Patients should be counselled regarding the risk of secondary malignancies and embryo-fetal toxicity.6
- Mechanism of action
EZH2 is a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) which catalyzes multiple methylations of lysine 27 on histone H3 (H3K27).6 Trimethylation of this lysine inhibits the transcription of genes associated with cell cycle arrest.3,6 PRC2 is antagonized by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex.3 Abnormal activation of EZH2 or loss of function mutations in SWI/SNF lead to hyper-trimethylation of H3K27.3 Hyper-trimethylation of H3K27 leads to cancer cell de-differentiation,1 a gain of cancer stem cell-like properties.2 De-differentiation can allow for cancer cell proliferation.1,2,3,6
Tazemetostat inhibits EZH2,6 preventing hyper-trimethylation of H3K27 and an uncontrollable cell cycle.3
Target Actions Organism AHistone-lysine N-methyltransferase EZH2 inhibitorHumans UHistone-lysine N-methyltransferase EZH1 inhibitorHumans - Absorption
Tazemetostat 800mg twice daily leads to a Cmax of 829ng/mL, with a Tmax of 1-2 hours , and an AUC of 3340ng*h/mL.4,6 Absorption is not significantly affected by a high fat, high calorie meal.6 Tazemetostat is 33% bioavailable.6
- Volume of distribution
Tazemetostat has a volume of distribution of 1230L.6
- Protein binding
Tazemetostat is 88% protein bound in plasma.6
- Metabolism
Tazemetostat is metabolized by CYP3A4 to an inactive desethyl metabolite and one other inactive metabolite not described.4,6
Hover over products below to view reaction partners
- Route of elimination
Tazemetostat is 15% eliminated in urine and 79% eliminated in feces.6
- Half-life
Tazemetostat has a terminal elimination half life of 3.1h.4,6
- Clearance
Tazemetostat has an apparent total clearance of 274L/h.6
- Adverse Effects
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Data regarding the presentation and management of tazemetostat overdoses are not readily available.6 The most common adverse reactions associated with tazemetostat are pain, fatigue, nausea, decreased appetite, vomiting, and constipation.6
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Tazemetostat can be increased when it is combined with Abametapir. Abatacept The metabolism of Tazemetostat can be increased when combined with Abatacept. Abemaciclib The excretion of Abemaciclib can be decreased when combined with Tazemetostat. Abrocitinib The serum concentration of Tazemetostat can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Tazemetostat. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Tazemetostat hydrobromide 6P89T5M073 1467052-75-0 UQRICAQPWZSJNF-UHFFFAOYSA-N - International/Other Brands
- Tazverik
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tazverik Tablet, film coated 200 mg/1 Oral Epizyme, Inc. 2020-01-23 Not applicable US 
Categories
- ATC Codes
- L01XX72 — Tazemetostat
- Drug Categories
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- Benzene Derivatives
- Benzoates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Substrates
- MATE 1 Inhibitors
- MATE 2 Inhibitors
- MATE 2-K Inhibitors
- MATE inhibitors
- Methyltransferase Inhibitor
- Methyltransferase Inhibitors
- Oxazines
- P-glycoprotein substrates
- Pyridines
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Biphenyls and derivatives
- Direct Parent
- Biphenyls and derivatives
- Alternative Parents
- Aminobenzamides / o-Toluamides / Benzamides / Benzoyl derivatives / Benzylamines / Phenylmethylamines / Dialkylarylamines / Aniline and substituted anilines / Aminotoluenes / Pyridinones show 16 more
- Substituents
- Amine / Amino acid or derivatives / Aminobenzamide / Aminobenzoic acid or derivatives / Aminotoluene / Aniline or substituted anilines / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzamide show 36 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- Q40W93WPE1
- CAS number
- 1403254-99-8
- InChI Key
- NSQSAUGJQHDYNO-UHFFFAOYSA-N
- InChI
- InChI=1S/C34H44N4O4/c1-5-38(29-10-14-41-15-11-29)32-20-28(27-8-6-26(7-9-27)22-37-12-16-42-17-13-37)19-30(25(32)4)33(39)35-21-31-23(2)18-24(3)36-34(31)40/h6-9,18-20,29H,5,10-17,21-22H2,1-4H3,(H,35,39)(H,36,40)
- IUPAC Name
- N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-4-methyl-4'-[(morpholin-4-yl)methyl]-[1,1'-biphenyl]-3-carboxamide
- SMILES
- CCN(C1CCOCC1)C1=C(C)C(=CC(=C1)C1=CC=C(CN2CCOCC2)C=C1)C(=O)NCC1=C(C)C=C(C)NC1=O
References
- General References
- Fu H, Cheng L, Sa R, Jin Y, Chen L: Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF(V600E) by synergistically decreasing global trimethylation of H3K27. J Cell Mol Med. 2020 Jan 22. doi: 10.1111/jcmm.15007. [Article]
- Friedmann-Morvinski D, Verma IM: Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 2014 Mar;15(3):244-53. doi: 10.1002/embr.201338254. Epub 2014 Feb 14. [Article]
- Makita S, Tobinai K: Targeting EZH2 with tazemetostat. Lancet Oncol. 2018 May;19(5):586-587. doi: 10.1016/S1470-2045(18)30149-9. Epub 2018 Apr 9. [Article]
- Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018 May;19(5):649-659. doi: 10.1016/S1470-2045(18)30145-1. Epub 2018 Apr 9. [Article]
- Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ, Porter-Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Uenaka T, Pollock RM, Kuntz KW, Yokoi A, Keilhack H: Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. doi: 10.1158/1535-7163.MCT-13-0773. Epub 2014 Feb 21. [Article]
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- External Links
- PubChem Compound
- 66558664
- PubChem Substance
- 347829042
- ChemSpider
- 30208713
- BindingDB
- 172038
- 2274378
- ChEMBL
- CHEMBL3414621
- ZINC
- ZINC000100285161
- Wikipedia
- Tazemetostat
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 200 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9090562 No 2015-07-28 2032-04-13 US US8410088 No 2013-04-02 2032-04-13 US US9394283 No 2016-07-19 2033-04-11 US US9872862 No 2018-01-23 2033-04-11 US US9522152 No 2016-12-20 2032-04-13 US US10369155 No 2019-08-06 2035-10-16 US US10420775 No 2019-09-24 2032-04-13 US US9855275 No 2018-01-02 2032-04-13 US US9549931 No 2017-01-24 2032-04-13 US US9688665 No 2017-06-27 2034-08-22 US US10245269 No 2019-04-02 2033-04-11 US US10155002 No 2018-12-18 2032-04-13 US US9889138 No 2018-02-13 2035-10-16 US US8765732 No 2014-07-01 2032-04-13 US US9334527 No 2016-05-10 2031-09-12 US US9333217 No 2016-05-10 2031-09-12 US US8691507 No 2014-04-08 2031-09-12 US US9175331 No 2015-11-03 2031-09-12 US US8895245 No 2014-11-25 2031-09-12 US US9949999 No 2018-04-24 2031-09-12 US US10786511 No 2020-09-29 2035-12-11 US US10821113 No 2020-11-03 2033-04-11 US US11052093 No 2021-07-06 2032-04-13 US US11491163 No 2013-04-11 2033-04-11 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 2.82 ChemSpider - Predicted Properties
Property Value Source Water Solubility 0.00932 mg/mL ALOGPS logP 4.44 ALOGPS logP 3.45 Chemaxon logS -4.8 ALOGPS pKa (Strongest Acidic) 11.64 Chemaxon pKa (Strongest Basic) 7.19 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 83.14 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 171.5 m3·mol-1 Chemaxon Polarizability 66.04 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 235.05847 predictedDeepCCS 1.0 (2019) [M+H]+ 237.45403 predictedDeepCCS 1.0 (2019) [M+Na]+ 243.36655 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2 (PubMed:22323599). Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription.
- Specific Function
- Chromatin binding
- Gene Name
- EZH2
- Uniprot ID
- Q15910
- Uniprot Name
- Histone-lysine N-methyltransferase EZH2
- Molecular Weight
- 85362.435 Da
References
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH1 complex, which methylates 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Required for embryonic stem cell derivation and self-renewal, suggesting that it is involved in safeguarding embryonic stem cell identity. Compared to EZH2-containing complexes, it is less abundant in embryonic stem cells, has weak methyltransferase activity and plays a less critical role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation.
- Specific Function
- Chromatin binding
- Gene Name
- EZH1
- Uniprot ID
- Q92800
- Uniprot Name
- Histone-lysine N-methyltransferase EZH1
- Molecular Weight
- 85270.37 Da
References
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
Enzymes
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Components:
| Name | UniProt ID |
|---|---|
| Cytochrome P450 3A4 | P08684 |
| Cytochrome P450 3A43 | Q9HB55 |
| Cytochrome P450 3A5 | P20815 |
| Cytochrome P450 3A7 | P24462 |
References
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018 May;19(5):649-659. doi: 10.1016/S1470-2045(18)30145-1. Epub 2018 Apr 9. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Zhang P, de Gooijer MC, Buil LC, Beijnen JH, Li G, van Tellingen O: ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors. Int J Cancer. 2015 Oct 15;137(8):2007-18. doi: 10.1002/ijc.29566. Epub 2015 Apr 24. [Article]
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Drug transmembrane transporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
- FDA Approved Drug Products: Tazverik (tazemetostat) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- Zhang P, de Gooijer MC, Buil LC, Beijnen JH, Li G, van Tellingen O: ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors. Int J Cancer. 2015 Oct 15;137(8):2007-18. doi: 10.1002/ijc.29566. Epub 2015 Apr 24. [Article]
Drug created at October 21, 2016 01:01 / Updated at March 10, 2022 09:37